7 Pharyngitis

David Jager and Matthew L. Mintz

CONTENTS CASE PRESENTATION KEY CLINICAL QUESTIONS LEARNING OBJECTIVES EPIDEMIOLOGY PATHOPHYSIOLOGY DIFFERENTIAL DIAGNOSIS DIAGNOSIS TREATMENT FUTURE DIRECTIONS REFERENCES

CASE PRESENTATION A 40-year-old woman presents to her primary care physician complaining of fever, malaise, and sore throat for the last 3 days. The patient has a past medical history significant for hypothyroidism. She takes only levothyroxine pills and recent thyroid tests have been normal. The patient denied nausea, vomiting, diarrhea, cough, chest pain, and shortness of breath. She is a nursery school teacher who reports having taken care of multiple children with “colds” in the recent week. She drinks one glass of wine every week and denied smoking or other drug use. The patient is married and lives with her husband, who has not been sick. Physical examination reveals a normal pulse and blood pressure, but a tem- perature of 101°F. She has no acute distress. Her turbinates are nonerythematous and her tympanic membranes appear normal. Her throat has erythematous tonsils bilaterally with white exudates and her neck reveals palpable anterior cervical adenopathy bilaterally. Her lungs are clear to auscultation bilaterally, with no wheezing, rales, or rhonchi. The remainder of her exam is normal.

From: Current Clinical Practice: Disorders of the Respiratory Tract: Common Challenges in Primary Care By: M. L. Mintz © Humana Press, Totowa, NJ 77 78 Part II / Disorders of the Upper Airway

KEY CLINICAL QUESTIONS 1. Can we make the diagnosis of group A streptococcus (GAS) pharyngitis on a clinical basis alone? 2. What is the differential diagnosis for pharyngitis? 3. Are there laboratory tests used to diagnose GAS? 4. What treatment modalities are available for pharyngitis?

LEARNING OBJECTIVES 1. Understand the proposed theories of how pharyngitis causes the symptoms of a “sore throat.” 2. Be familiar with the laboratory tests and clinical findings used to diagnose GAS pharyngitis. 3. List the differential diagnosis of viral, bacterial, and fungal causes of pharyngitis. 4. Know the different treatment options available for GAS pharyngitis as well as other causes of pharyngitis.

EPIDEMIOLOGY Pharyngitis is an inflammatory process of the pharynx, hypopharynx, uvula, and tonsils. Acute pharyngitis is one of the most common causes of physician visits, accounting for 2% of ambulatory visits in the United States every year (1). In adults, GAS is found in only 10% of patients who seek medical attention. Although the majority of causes of pharyngitis do not require treatment with antibiotics, the majority of patients nonetheless receive them. According to the National Ambulatory Medical Care Survey, 18 million patients sought care for a sore throat in the United States during 1996 (2). Therefore, because approximately 75% of patients who see physicians for pharyngitis receive antibiotics (3), the treatment of pharyngitis is a major cause of excess antibiotic use in the United States. In addition to side effects from medications, the consequences of unnec- essary antibiotic use have led to more resistant bacterial organisms. Upper respiratory infections are the most common cause of illness. During the 1990s, an average of 6.5 million adults presented as outpatients with the chief complaint of sore throat in the United States (4). Children are affected more often than the adult population. GAS (Streptococcus pyogenes) accounts for 15–36% of pediatric cases of pharyngitis. It has been estimated that children between the ages of 6 months and 2 years who are in day care have an upper respiratory infection approximately every 3 weeks (5). A large portion of these infections are pharyngitis. Chapter 7 / Pharyngitis 79

PATHOPHYSIOLOGY Pharyngitis is frequently found in the setting of a viral upper respiratory infection. The pathogenesis of pharyngitis is not well-understood, but many theories have been offered. When a group of volunteers were given rhinoviral infections, bradykinin and lysylbradykinin were produced. These are known inflammatory mediators that can excite nerve endings in the pharynx, resulting in pain (5). Other research done with laboratory animals found that viral infections produced an inflammatory response by invading pharyngeal cells (4). Adenovirus and Epstein-Barr virus produce lymphoid hyperplasia and tonsilar exudates (4). Herpes simplex virus causes oral mucosa ulcerations that are frequently found in the anterior portion of the mouth. In contrast, coxsackievirus causes oral ulcers located in the posterior mouth and pharynx. Pharyngitis caused by streptococcus B produces inflammation of the posterior pharynx. In patients with Epstein-Barr virus, as many as 10% of patients will have a GAS superinfec- tion (4). In some patients with Corynebacterium diphtheriae pharyngitis, a gray membrane can be seen over the posterior pharynx. GAS (S. pyogenes) is transmitted through inhalation or contact with secretions (6). Studies have shown that if a person is colonized with S. pyogenes, then 10% of family members will become colonized (7). If that person has symptomatic pharyngitis, the percentage of family members who will become colonized increases to 25% (8). Research has shown that school-age children are most likely the initial carriers of streptococcus into the family unit (6). In patients who are colonized, 40% will develop streptococcal pharyngitis (7). Differentiating streptococcal pharyngitis from other causes is important because GAS is the only major organism to which antibiotic therapy should be directed. GAS infection also has associated infections regarded as complications. These complications include acute rheumatic fever, toxic shock syndrome, and acute glomerulonephritis. Acute rheumatic fever occurs after a latent period of 2 to 3 weeks after the pharyngitis begins. Symptoms of acute rheumatic fever include carditis, arthritis, chorea, erythema marginatum, and subcutaneous nodules. During World War II, the incidence of rheumatic fever among US army person- nel reached 388 cases per 100,000 at its apex (9). Secondary to improved antibiotics, increased access to health care, and decreased crowding, the incidence fell to 0.23 to 1.14 cases per 100,000 school-aged children during the 1970s and 1980s (10). The current annual incidence of rheumatic fever is approximately one case per 1 million people (10). Streptococcal toxic shock syndrome is rarely associated with pharyngitis. The site of initial infection is commonly localized to skin, vagina, pharynx, and mucosa but in 45% of cases, no portal of entry can be determined (11). 80 Part II / Disorders of the Upper Airway

Timely therapeutic intervention to treat GAS pharyngitis does not prevent acute poststreptococcal glomerulonephritis (APG), the most common cause of postinfectious glomerulonephritis (12). APG is a common cause of acute and chronic renal failure in children (13). APG is most commonly found between the ages of 2 and 12 (12). Although commonly found in the pediatric population, 5 to 10% of APG is found in patients ages 49 and older (14). There is a male- to-female ratio of 2:1 in APG (13). The glomerulonephritis develops 10 days after pharyngitis (15). Some patients present with nephritic syndrome, whereas others present with hematuria. In more than 90% of patients with APG, the presentation is that of acute nephritic syndrome (16). The average risk of devel- oping APG following GAS infection is 15%, but during epidemics that risk can increase to 25% (14). APG is an acute inflammatory disorder of the glomerulus initiated by GAS (12). The development of APG is likely dependent on the virulence of the bacterial strain and the immune response created by the patient.

DIFFERENTIAL DIAGNOSIS Sore throat is one of the most common complaints of adults in the outpatient setting. The differential diagnosis includes thyroiditis, gastroesophageal reflux, oropharyngeal/laryngeal tumor, pharyngitis, peristonsillar abscess, epiglottitis, retropharyngeal abscess, and Ludwig angina. However, the majority of patients with a “sore throat” will have pharyngitis. The differential diagnosis for causative agents of pharyngitis is extremely diverse as shown in Table 1. Viruses are estimated to cause roughly 30% of pharyngitis cases (17). Rhi- novirus is the most common viral cause. The other common viral causes in descending order are coronavirus, adenovirus, parainfluenza, and influenza virus (18). Viral infections are more common during the winter months with the exception of adenoviruses, which occur year round. Patients with influenza can be diagnosed secondary to other cases in the community. The differential includes acute retroviral syndrome, which may be difficult to differentiate from mononucleosis. In patients in which HIV is in the differential diagnosis, risk factors for HIV must be explored by the physician. The symptoms may develop from 6 days to 3–5 weeks depending on the length of incubation. The symptoms of acute retroviral syndrome include pharyngitis, lymphadenopathy, fever, myalgia, and lethargy (19). Herpes virus type I has been noted to cause a pharyngitis, as well as herpes virus type 2 if oral–genital contact has occurred. Infectious mononucleosis is another viral infection that can cause pharyngitis. The majority of cases of mononucleosis are caused by Epstein-Barr virus with the remainder of cases caused by cytomegalovirus. Pharyngitis and tonsillar exudates in addition to lymphadenopathy, fatigue, and splenomegally point to a diagnosis of mononucleosis. Viral pharyngitis is spread through similar mecha- Chapter 7 / Pharyngitis 81

Table 1 Causes of Pharyngitis Bacteria Arcanobacterium haemolyticum Corynebacterium diptheriae Corynebacterium other spp. Haemophilus influenzae Legionella pneumophilia Neisseria gonorrhoeae Neisseria meningitides Streptococcus pyogenes (group A b- hemolytic) Streptococcus spp. (groups B, C, and G) Treponema palidum Yersinia enterolitica Fungal/rickettsial/intracellular organisms Candida spp. Mycoplasma pneumoniae Coxiella burnettii Chlamydia pneumoniae Viruses Adenovirus Coronavirus Coxsackie A virus Cytomegalovirus Epstein-Barr virus Herpes simplex virus Human immunodeficiency virus-1 Influenza A and B Parainfluenza Measles Reovirus Respiratory syncytial virus nisms as other viral infections. Hand-to-mouth contact, contact with oral secretions, and sharing common utensils all contribute to viral spread. Prevention of the spreading of disease is based on frequent hand washing and avoidance of aerosolized secretions. Mycoplasma and chlaymdia typically cause pharyngitis in young patients with acute bronchitis. Streptococci groups C and G are responsible for food- and water-borne pharyngitis outbreaks (19). These bacteria have also been documented to cause a less severe form of pharyngitis that mimics GAS. These organisms commonly colo- nize the respiratory tract, therefore, differentiating this state from acute infection is often difficult. Arcanobacterium haemolyticum produces a pharyngitis that is difficult to distinguish from GAS pharyngitis (19). A. haemolyticum infection 82 Part II / Disorders of the Upper Airway should be suspected in adolescents and young adults with a clinical presentation consistent with GAS but with a negative culture. Diphtheria was once a more common cause of pharyngitis in the United States, but is now rare. One probable case was reported to the Centers for Disease Control and Prevention (CDC) in 1998 (19). With the advent of immunization, diphtheria cases are now rare in industrialized nations. Pharyngeal infection with C. diphtheriae produces a grayish-brown membrane on the pharynx, uvula, and larynx. Diagnosis is usually made based on clinical and epidemiological factors.

DIAGNOSIS The majority of cases of viral pharyngitis are associated with an upper respiratory infection. An upper respiratory infection commonly begins with malaise, fever, headache, myalgias, and then coryza and sore throat. In assessing patients with pharyngitis, there is great importance in differentiating GAS from all other causes. Research has showed that physicians are poor predictors of which patients will have positive throat cultures for GAS pharyngitis. The sensitivity and specificity range from 55 to 74% and 58 to 76%, respectively (1). The Centor criteria were created to aid physicians in diagnosing GAS. The four criteria are tonsillar exudates, history of fever, absence of cough, and tender anterior cervical adenopathy. If three or four criteria are met, the positive predictive value is 40 to 60% (20). The negative predictive value of less than three criteria is 80% (20). The sensitivity and specificity are both increased to approximately 75% when the criteria are implemented according to some studies (21). Clinical features that are consistent with GAS pharyngitis include sore throat, sudden onset of symptoms, fever, and headache. Clinical symptoms consistent with a viral etiology include conjunctivitis, coryza, cough, and diarrhea. The CDC has released principles to govern diagnosing and treating patients with GAS. The CDC recommends that all adult patients with pharyngitis should be screened with the Centor criteria. If patients have none or one criterion, these patients shouldn’t be tested or treated because they are unlikely to have GAS (22). When patients have two, three, or four criteria, a rapid antigen test (RAT) should be performed. If the RAT is positive, then antibiotic therapy should be started. The algorithm that we recommend is to test patients with two or three criteria with an RAT, and treat those with a positive test and those with four criteria. The final option is to not use diagnostic tests and use antibiotics to treat patients with three or four criteria (22). The guidelines do not apply to immunocompromised patients and patients with a history of rheumatic fever, valvular heart disease, sore throats not caused by acute pharyngitis, and patients that have recurrent or chronic pharyngitis (22). The guidelines do not apply during outbreaks of GAS. The diagnosis of acute GAS pharyngitis in children should be similarly based on clinical grounds and then verified by RAT or throat culture. There is great Chapter 7 / Pharyngitis 83 debate as to what clinical guidelines should be implemented. We recommend using the Centor criteria (fever, tonsillar exudates, absence of cough, cervical lymphadenopathy) as well as including seasonal risk factors (November to May) and personal or family contact history of rheumatic fever. If a patient has one or less of these criteria, GAS is less likely, so no further testing or treatment is needed. For two or more criteria, we recommend either RAT or throat culture. The Infectious Disease Society of America recommends that if a child has a negative RAT, it must be confirmed by a throat culture. If either the RAT or throat culture are positive, then treatment must be started (23). The gold standard for diagnosis of GAS is the throat culture. The drawbacks of traditional throat cultures have been the 24 to 48 hours required for growth. This duration of time makes decisions about whether to start antibiotics difficult. Other criticisms include the insensitivity of the test secondary to variations in specimen collection and laboratory processing (24). Another drawback of throat cultures is the false-positives secondary to 5% carrier rate for GAS (25). Plating of the specimen is to occur under direct visualization of the specimen with immediate plating onto sheep’s blood agar with low dextrose content. With proper technique, sensitivity and specificity in adults are at least 90%, but in clinical practice, sensitivity and specificity are significantly lower. The delay in information provided by standard throat cultures makes their usefulness of question. The advent of the RAT has provided faster results that can be given at the bedsides and done quickly in office labs. Most rapid streptococcus tests detect the surface carbohydrate that designates a streptococcus as a member of Lancefield group A. The early tests used latex agglutination methods, whereas the second-generation tests employed enzyme immunoassays. Modern tests use DNA probes and optical immunoassays (26). Recent studies have showed sensitivity of 80 to 90% and specificity of 90 to 100% (27). The American Academy of Pediatrics has guidelines that consider a positive RAT to be considered defini- tive evidence of streptococcal pharyngitis (28). If the RAT is negative, but there is strong clinical suspicion, then a standard throat culture should be performed. Serological testing is of little use in the diagnosis of streptococcal pharyngitis. In the picture of acute streptococcal pharyngitis, a fourfold rise in antistrep- tolysin or anti-deoxyribonuclease B may be seen. The titers will rise during acute infection and will peak within 2 weeks. The serological results are not present when treatment decisions must be made.

TREATMENT There are numerous factors that influence selecting an antibiotic treatment for streptococcal pharyngitis. These factors include bacteriological and clinical ef- ficacy, patient allergies, compliance concerns, and frequency of drug adminis- tration, palatability, cost, spectrum of activity, and side effects (9). Table 2 lists some of the potential antibiotic choices. 84 Part II / Disorders of the Upper Airway

Table 2 Antibiotic Treatment for Group A β-hemolytic Streptococcal Pharyngitis Penicillin V Penicillin G benzathine Amoxicillin Erythromycin ethylsuccinate Erythromycin estolate Azithromycin Amoxicillin-clavulanate potassium Cefadroxil Cephalexin

Penicillin has been the drug of choice for streptococcal pharyngitis in both adults and children. Initially, GAS pharyngitis was treated with a single injection of penicillin G benzathine. Studies conducted in the 1960s and 1970s have shown that oral and intramuscular penicillin were equally effective treatment regimens (9). Based on this information, oral penicillin V has been the treatment of choice since the 1980s (29). Drawbacks to penicillin use are allergic reactions and compliance with four times daily dosing regimen. Studies have shown that clinical failure rates range from 5 to 15% and bacteriological failure rates range from 10 to 30% (30). Adults with GAS pharyngitis should be given penicillin V 500 mg orally two or three times daily for 10 days or one intramuscular injection of penicillin. Children should receive penicillin V 250 mg orally two or three times daily for 10 days. Amoxicillin has benefit over penicillin of having longer half-life and improved palatability. Skin rashes and gastrointestinal side effects are more common with amoxicillin (9). The first-line alternative for patients with a penicillin allergy is erythromycin. The gastrointestinal side effects cause 15 to 20% of patients to be unable to tolerate erythromycin therapy (31). Azithromycin is an alternative treatment with fewer side effects than erythromycin, but is much more expensive. Cephalosporins have been found to be superior to penicillin V in a meta- analysis of 19 trials. The bacteriological cure rate for cephalosporins was 92% compared with 84% for penicillin (32). The first-generation cephalosporins are preferred over the second- or third-generation antibiotics. The cost and penicillin crossreactivity make cephalosporins less desirable for first-line treatment of streptococcal pharyngitis. The broadest spectrum antibiotic choice is amoxicillin- clavulanate potassium, which is expensive and has diarrhea as a side effect. Amoxicillin-clavulanate is typically used to treat recurrent streptococcal pharyngitis (33). Chapter 7 / Pharyngitis 85

A chart review study found that recurrent group A β-hemolytic streptococcal infections were more common in the 1990s than in previous decades (34). It is unclear whether patients have a relapse of the initial infection or are becoming re-infected. Numerous theories have been created to explain these findings, which include lack of compliance, repeat exposure, eradication of protective pharyngeal microflora, penicillin resistance, and antibiotic suppression of immunity (30). In patients with continued infection, other reservoirs of infection must be examined. Group A β-hemolytic streptococci can persist for up to 15 days on unrinsed toothbrushes and orthodontic appliances (35). Thorough rinsing of these items may decrease spread of infection and help to prevent re-infection. There is no need to repeat throat cultures following treatment. If a patient has a positive posttreatment culture, it means that the patient is a chronic carrier and is of little concern to spread infection. Chronic carriers will only be treated if they are associated with treatment failure in a close contact (9). The CDC recommends that throat cultures should not be used for screening adults with pharyngitis or used for confirmation of negative rapid tests when the test sensitivity exceeds 80% (22). Another treatment recommendation is that all patients with pharyngitis should be offered analgesics, antipyretics, and other supportive care.

FUTURE DIRECTIONS The future of diagnosis of GAS pharyngitis involves the development of more rapid tests using optical immunoassay and chemiluminescent DNA (9). These tests will increase the accuracy of diagnosis, but will likely be more costly. Research is currently underway to create a vaccine to prevent the disease. The target for the vaccine is the streptococcal M protein, but this research will take many years to potentially reach the market (36). Future research may also need to be directed into recurrences of infection and changing drug sensitivities.

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